Homozygous sickle cell disease is a major problem throughout the United States and world that results in vaso-occlusive events, a variety of secondary disease complications, and a reduced life expectancy. HbSS is a genetic disorder characterized by the sickling of red blood cells (RBCs) due to the replacement of glutamic acid with valine in position 6 on the B chains of hemoglobin. As a result of this structural change, the life span of the RBC is greatly reduced from the normal 120 days to approximately 10 days. The sickling of RBCs leads to a chronic anemia and increased RBC catabolism and synthesis. These physiological perturbations have the potential to promote increased energy expenditure, increased protein breakdown and synthesis, increased anaerobic metabolism and altered insulin action. Each of these metabolic derangements is capable of altering specific substrate oxidation and increasing protein and energy demands. The specific aim of the proposed research is to determine the impact of HbSS on whole-body and skeletal muscle insulin-mediated metabolism. These experiments will use HbSS patients with isotopic tracer techniques, indirect calorimetry, and euglycemic-hyperinsulinemic clamps. To date we have completed one study, and these preliminary results suggest that insulin-mediated glucose utilization is enhanced. When combined, the proposed protocols will increase our understanding of how HbSS alters protein and energy metabolism and will identify mechanisms for these alterations. The contributions of HbSS to health care costs is significant, and the knowledge gained from these studies will enable us to better understand the various metabolic disease processes associated with HbSS. This knowledge will assist in the design of appropriate nutritional regimens, thereby culminating in better disease outcomes.